Endocannabinoid system involvement in brain reward processes related to drug abuse

Abstract

Cannabis is the most commonly abused illegal drug in the world and its main psychoactive ingredient, delta-9-tetrahydrocannabinol (THC), produces rewarding effects in humans and non-human primates. Over the last several decades, an endogenous system comprised of cannabinoid receptors, endogenous ligands for these receptors and enzymes responsible for the synthesis and degradation of these endogenous cannabinoid ligands has been discovered and partly characterized. Experimental findings strongly suggest a major involvement of the endocannabinoid system in general brain reward functions and drug abuse. First, natural and synthetic cannabinoids and endocannabinoids can produce rewarding effects in humans and laboratory animals. Second, activation or blockade of the endogenous cannabinoid system has been shown to modulate the rewarding effects of noncannabinoid psychoactive drugs. Third, most abused drugs alter brain levels of endocannabinoids in the brain. In addition to reward functions, the endocannabinoid cannabinoid system appears to be involved in the ability of drugs and drug-related cues to reinstate drug-seeking behavior in animal models of relapse. Altogether, evidence points to the endocannadinoid system as a promising target for the development of medications for the treatment of drug abuse.

Discriminative stimulus functions in rats of AM1346, a high-affinity CB1R selective anandamide analog

“…Limited drug-like responding in tests with D-amphetamine and morphine also occurred in rats trained with lower (1.8 mg/kg) and higher (5.6 mg/kg) doses of Δ 9 -THC, as well as in rats trained with 10 mg/kg mAEA (Järbe et al 1998a(Järbe et al , 2006). Yet, mAEA has been reported to augment methamphetamine self-administration in rodents (Vinklerová et al 2002), and in common with other drugs of abuse, CB 1 R agonists have been shown to result in increased dopamine levels in the nucleus accumbens (discussed in Solinas et al 2007b). Although speculative, such commonality in end result might have been a contributing factor for the relatively high degree of drug-like responding observed with Damphetamine in the rats discriminating between 3 mg/kg AM1346 and vehicle.…”

Neurobiological mechanisms of cannabinoid addiction

“…In addition, inhibition of the fatty acid amide (FAAH) by URB597, but not inhibition of AEA transport by AM404 or UCM707, considerably potentiates both the duration and the magnitude of the AEA-induced DA rise, suggesting brain specificity for FAAH versus transport/FAAH inactivation of AEA (Solinas et al, 2006(Solinas et al, , 2007b.…”

“…More recently, it has been reported that AEA also possesses the ability to produce a fast and significant elevation in extracellular DA levels in the shell of the NAc when injected intravenously (Solinas et al, 2006(Solinas et al, , 2007b. In addition, inhibition of the fatty acid amide (FAAH) by URB597, but not inhibition of AEA transport by AM404 or UCM707, considerably potentiates both the duration and the magnitude of the AEA-induced DA rise, suggesting brain specificity for FAAH versus transport/FAAH inactivation of AEA (Solinas et al, 2006(Solinas et al, , 2007b.…”

Neurobiologia da Cannabis: do sistema endocanabinoide aos transtornos por uso de Cannabis

“…Isso significa que o resultado final será dependente do set (contexto interior) e setting (contexto ambiental) (Figura 3). Dessa forma, pode-se entender as diferentes consequências associadas ao uso terapêutico ou hedonístico da Cannabis, incluindo a transição (ou não) de uso experimental para hedonístico e os diferentes padrões de uso recreacional 71 . A modulação dopaminérgica do eixo ATV-FPM-NAc no NAc ocorre de forma bastante similar, podendo ocorrer modulação direta e indireta 40,67,69,70 .…”